PROJECT SUMMARY_OVERALL Aging- related challenges, including alterations in mood, sleep disturbances and cognitive decline, have detrimental effects on quality of life for the elderly. Many botanical agents are purported to improve resilience to these changes, yet few have been evaluated in well-designed clinical trials. An ideal clinical trial would use a product optimized for its active constituents, and investigate the botanical for appropriate measures of efficacy in a relevant target population. Sound preclinical research is therefore needed to identify the functional effects of a botanical, mechanisms underlying these effects, and the phytochemical constituents modulating these processes. Studies should also identify interactions between different constituents of botanical, in vivo biomarkers of target engagement by the botanical, distribution of the compounds in the body, and variability of response in different populations e.g. age or gender groups. The proposed Botanical Dietary Supplement Research Center (BDSRC) will establish a pipeline of experimental approaches and techniques required to deliver answers to these critical issues, with a focus on ?Botanicals enhancing neurological and functional resilience in aging?. This research platform will be used to consolidate and expand our extensive preliminary studies on Centella asiatica (CA; ?gotu kola?), in preparation for a clinical trial in aging participants. A second botanical, Withania somnifera (WS; ?ashwagandha?), with compelling reports of similar biological effects to CA will be examined in earlier stages of the research pipeline. The specific aims of the Center are to (1) to ensure a reliable supply of CA and WS and develop methods for targeted and untargeted analysis of their constituents in plant extracts, plasma and brain tissue; (2) to investigate the in vivo effects of CA and currently known active compounds on cognition, sleep disturbance and mood in mice, and identify in vivo biomarkers relating to these effects; (3) to explore mechanisms and active compounds of CA and WS extracts through targeted and untargeted approaches including biochemometric correlations of composition with biological activity, and metabolomics or transcriptomics of treated target tissues. These goals will be achieved by the synergistic interaction of a Botanical Core, Research Project 1 examining in vivo effects of CA on cognition, sleep deprivation and mood and Research Project 2 exploring mechanisms and active compounds of CA and WS using mouse primary neurons in vitro, mouse brain slices ex vivo and Drosophila melanogaster in vivo. An Administrative Core will co-ordinate, guide and disseminate the research activities of the BDSRC, and provide data management and statistical support. It will also coordinate aim (4) which is to provide research training and career development opportunities to graduate students and postdoctoral scientists. The BDSRC?s pipeline will, in future, include clinical trials performed at the NIH/Layton Aging and Alzheimer?s Center at OHSU.